GDF11

Summary

GDF11 (growth differentiation factor 11, HGNC:4216) is a protein-coding gene on chromosome 12q13.2, encoding Growth/differentiation factor 11 (O95390). Secreted signal that acts globally to regulate anterior/posterior axial patterning during development.

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein plays a role in the development of the nervous and other organ systems, and may regulate aging.

Source: NCBI Gene 10220 — RefSeq curated summary.

At a glance

• Gene–disease (curated): vertebral hypersegmentation and orofacial anomalies (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 52 total
• Phenotypes (HPO): 22
• MANE Select transcript: NM_005811

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4216
Approved symbol	GDF11
Name	growth differentiation factor 11
Location	12q13.2
Locus type	gene with protein product
Status	Approved
Aliases	BMP-11, BMP11
Ensembl gene	ENSG00000135414
Ensembl biotype	protein_coding
OMIM	603936
Entrez	10220

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000257868, ENST00000546799

RefSeq mRNA: 1 — MANE Select: NM_005811 NM_005811

CCDS: CCDS8891

Canonical transcript exons

ENST00000257868 — 3 exons

Exon	Start	End
ENSE00000920147	55743122	55743761
ENSE00000920148	55748586	55748983
ENSE00000920149	55749502	55757264

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 93.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.8889 / max 78.3818, expressed in 1546 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125985	3.6327	1406
125986	3.2562	1112

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	93.71	gold quality
retina	UBERON:0000966	93.69	gold quality
medial globus pallidus	UBERON:0002477	89.06	gold quality
tendon of biceps brachii	UBERON:0008188	88.88	gold quality
globus pallidus	UBERON:0001875	88.47	gold quality
ventral tegmental area	UBERON:0002691	88.12	gold quality
subthalamic nucleus	UBERON:0001906	87.21	gold quality
buccal mucosa cell	CL:0002336	86.89	gold quality
superior vestibular nucleus	UBERON:0007227	86.61	gold quality
endothelial cell	CL:0000115	86.38	gold quality
vena cava	UBERON:0004087	86.38	gold quality
pons	UBERON:0000988	86.32	gold quality
stromal cell of endometrium	CL:0002255	86.02	gold quality
lateral globus pallidus	UBERON:0002476	85.61	gold quality
inferior vagus X ganglion	UBERON:0005363	85.30	gold quality
substantia nigra pars compacta	UBERON:0001965	84.96	gold quality
lateral nuclear group of thalamus	UBERON:0002736	84.59	gold quality
cardia of stomach	UBERON:0001162	84.37	gold quality
substantia nigra pars reticulata	UBERON:0001966	84.21	gold quality
amygdala	UBERON:0001876	83.33	gold quality
dorsal plus ventral thalamus	UBERON:0001897	82.89	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	82.61	gold quality
spinal cord	UBERON:0002240	82.05	gold quality
temporal lobe	UBERON:0001871	81.97	gold quality
cortical plate	UBERON:0005343	81.71	gold quality
body of tongue	UBERON:0011876	81.66	silver quality
putamen	UBERON:0001874	81.32	gold quality
dorsal root ganglion	UBERON:0000044	81.03	gold quality
trigeminal ganglion	UBERON:0001675	80.86	gold quality
superior surface of tongue	UBERON:0007371	80.64	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.35
E-HCAD-13	no	2.91

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXG1

miRNA regulators (miRDB)

163 targeting GDF11, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-95-5P	99.89	72.17	3973

Literature-anchored findings (GeneRIF, showing 40)

• Quantitative real-time reverse transcription-PCR in colorectal cancer specimens obtained from 130 patients showed that GDF11 mRNA expression in cancer tissue was significantly higher than in normal tissue (PMID:17912435)
• Members of the transforming growth factor beta (TGFbeta) superfamily, bone morphogenetic protein 2 (BMP2), and growth and differentiation factor 11 (GDF11), can signal cultured RGCs to form dendrites. (PMID:17997109)
• We propose that Pcsk5, at least in part via GDF11, coordinately regulates caudal Hox paralogs, to control anteroposterior patterning, nephrogenesis, skeletal, and anorectal development. (PMID:18519639)
• Differential antagonism of activin, myostatin and growth and differentiation factor 11 by wild-type and mutant follistatin. (PMID:18535106)
• Both WFIKKN1 and WFIKKN2 have high affinity for growth and differentiation factors 8 and 11. (PMID:18596030)
• Myostatin or 20 ng/mL BMP-11 maintain the colony and cellular morphology of undifferentiated hESC, maintain POU5f1, NANOG, TRA-1-60, and SSEA4 expression, and display increased SMAD2/3 phosphorylation (PMID:19751112)
• These data demonstrate GDF11 to be a master regulator of neural stem cell transcription that can suppress cell proliferation and migration by regulating the expression of numerous genes involved in both these processes (PMID:24244313)
• Expression of GDF11, a cytokine which blocks terminal erythroid maturation, was increased in erthyroblasts of thalassemic patients. (PMID:24658077)
• Suggest GDF11 functions as encephalic regionalizing factor in neural differentiated mouse embryonic stem cells. (PMID:25352416)
• GDF11 is a critical rheostat for bone turnover and a key integrator of bone homeostasis. (PMID:25534870)
• GDF11 inhibits rather than helps muscle regeneration. (PMID:26001423)
• in vitro sprout formation was increased as well by GDF11 treatment (PMID:26026854)
• Show that there is no age-related cardiac hypertrophy in disease-free 24-month-old C57BL/6 mice and that restoring GDF11 in old mice has no effect on cardiac structure or function. (PMID:26383970)
• The crystal structure of GDF11 was determined to a resolution of 1.50 A. (PMID:26919518)
• GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues. It functions in the heart, skeletal muscle, and brain. Review. (PMID:27034275)
• MSTN, but not GDF11, declines in healthy men throughout aging. (PMID:27304512)
• GDF11 is highly concentrated in human platelets. (PMID:27509407)
• In elderly Chinese women, osteoporosis risk was significantly increased with increases in GDF11 serum levels. (PMID:27557752)
• These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined. (PMID:28257634)
• The Growth Differentiation Factor 11 (GDF11) and Myostatin (MSTN) in tissue specific aging. (PMID:28472635)
• GDF11 may be a relevant myostatin-interacting peptide to successful aging in humans (PMID:28701523)
• A Prodomain Fragment from the Proteolytic Activation of Growth Differentiation Factor 11 Remains Associated with the Mature Growth Factor and Keeps It Soluble (PMID:28715204)
• Tumor-suppressor inactivation of GDF11 occurs by precursor sequestration in triple-negative breast cancer (PMID:29161592)
• GDF11 expression was decreased in COPD patients’ serum and cells when compared with that of healthy people. (PMID:29680737)
• Physical inactivity was significantly related to the decreased GDF11 levels in COPD. (PMID:29731621)
• Plasma levels of GDF11 had a higher association with body mass and body composition than muscle function in older women. (PMID:30165829)
• The serum content of GDF11 was much less in esophageal cancer patients than in the control group. Esophageal GDF II in cancer patients was correlated with cancer differentiation: the higher the degree of differentiation, the higher the content of GDF11. (PMID:30213293)
• Growth differentiation factor 11 was independent predictor of BMD in girls with with anorexia nervosa. Results suggested that GDF11 exerts a negative effect on bone mass. (PMID:30281844)
• Results show that GDF11 expression and activity were reduced in skin dermal fibroblasts deriving from adult donors compared to neonatal ones supporting the conclusions of GDF11 being an anti-ageing factor in humans. (PMID:30661170)
• GDF11 and SIRT1 were strongly inter-correlated, suggesting common upstream regulators. Leukocyte telomere lengths (LTLs) were moderately correlated to GDF11 and SIRT1 in overweight women, which may reflect common life-style influences on LTLs and these markers. (PMID:30684534)
• Serum GDF11 levels were increased and negatively correlated with Hb levels and reticulocyte counts in AA patients. This suggests an impaired GDF11 response contributing to anemia in AA patients. (PMID:30727851)
• methylation modulated GDF11 expression might be a valuable prognostic biomarker regarding OS in uveal melanoma. (PMID:30883611)
• Study demonstrate that colorectal cancer (CRC)-associated human intestinal lymphatic endothelial cells (HILEC) regulate tumor cell growth via the soluble matrisome component Growth Differentiation Factor 11 (GDF11), pointing to an unconventional role of lymphatics in controlling CRC growth and progression aside from their classical role as conduit of metastasis. (PMID:30889293)
• GDF11 exhibits tumor suppressive properties in hepatocellular carcinoma cells by restricting clonal expansion and invasion. (PMID:30890427)
• Circulating GDF11 levels are decreased with age but no significant differences in circulating concentrations of GDF11 regarding obesity or glycemic status were found. Serum GDF11 concentrations in humans decrease in older ages being unaltered in obesity and T2D. (PMID:30897065)
• GDF11 inhibits adipogenic differentiation. (PMID:31038259)
• A Renewed Focus on GDF11 Level Fluctuation in Human Serum in Relation to Physical Examination Indicators. (PMID:31120107)
• A review of the GDF11 literature, as it relates in particular to aging and skeletal muscle, cardiac and bone biology, is presented. [review] (PMID:31144559)
• This work, for the first time, demonstrates an important role for GDF11 in skin biology and a potential impact on skin health and aging. (PMID:31181098)
• the unique association of orofacial clefting and vertebral/rib hypersegmentation with GDF11 warrants this presentation to be now classified as a novel syndromic form of orofacial clefting. (PMID:31215115)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gdf11	ENSMUSG00000025352
rattus_norvegicus	Gdf11	ENSRNOG00000007610

Paralogs (31): TGFB2 (ENSG00000092969), BMP7 (ENSG00000101144), TGFB1 (ENSG00000105329), BMP5 (ENSG00000112175), BMP8B (ENSG00000116985), TGFB3 (ENSG00000119699), INHBA (ENSG00000122641), INHA (ENSG00000123999), BMP4 (ENSG00000125378), BMP2 (ENSG00000125845), GDF5 (ENSG00000125965), GDF1 (ENSG00000130283), BMP15 (ENSG00000130385), GDF15 (ENSG00000130513), MSTN (ENSG00000138379), INHBE (ENSG00000139269), LEFTY2 (ENSG00000143768), GDF7 (ENSG00000143869), BMP3 (ENSG00000152785), BMP6 (ENSG00000153162), GDF6 (ENSG00000156466), NODAL (ENSG00000156574), INHBB (ENSG00000163083), BMP10 (ENSG00000163217), GDF9 (ENSG00000164404), INHBC (ENSG00000175189), BMP8A (ENSG00000183682), GDF3 (ENSG00000184344), LEFTY1 (ENSG00000243709), GDF2 (ENSG00000263761), GDF10 (ENSG00000266524)

Protein

Protein identifiers

Growth/differentiation factor 11 — O95390 (reviewed: O95390)

Alternative names: Bone morphogenetic protein 11

All UniProt accessions (2): O95390, H0YI30

UniProt curated annotations — full annotation on UniProt →

Function. Secreted signal that acts globally to regulate anterior/posterior axial patterning during development. May play critical roles in patterning both mesodermal and neural tissues. It is required for proper vertebral patterning and orofacial development. Signals through activin receptors type-2, ACVR2A and ACVR2B, and activin receptors type-1, ACVR1B, ACVR1C and TGFBR1 leading to the phosphorylation of SMAD2 and SMAD3.

Subunit / interactions. Homodimer; disulfide-linked. Interacts directly with ACVR2B. Interacts directly with ACVR2A. Interacts with ACVR1B, TGFBR1 and ACVR1C in an ACVR2B-dependent manner. Interacts with FST isoform 2/FS-288.

Subcellular location. Secreted.

Tissue specificity. In the embryo, strong expression is seen in the palatal epithelia, including the medial edge epithelial and midline epithelial seam of the palatal shelves. Less pronounced expression is also seen throughout the palatal shelf and tongue mesenchyme.

Post-translational modifications. Synthesized as large precursor molecule that undergoes proteolytic cleavage by furin-like proteases. This produces an inactive form consisting of the mature C-terminal portion non-covalently bound to its cleaved N-terminal propeptide. Activation of the mature form requires additional cleavage of the propeptide by a tolloid-like metalloproteinase.

Disease relevance. Vertebral hypersegmentation and orofacial anomalies (VHO) [MIM:619122] An autosomal dominant disease characterized by supernumerary ribs, supernumerary cervical, thoracic and/or lumbar vertebrae, and orofacial anomalies such as cleft lip with or without cleft palate in most patients. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TGF-beta family.

RefSeq proteins (1): NP_005802* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001111	TGF-b_propeptide	Domain
IPR001839	TGF-b_C	Domain
IPR015615	TGF-beta-like	Family
IPR017948	TGFb_CS	Conserved_site
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00019, PF00688

UniProt features (26 total): strand 11, disulfide bond 5, turn 2, site 2, signal peptide 1, propeptide 1, sequence variant 1, chain 1, helix 1, glycosylation site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5E4G	X-RAY DIFFRACTION	1.5
5UHM	X-RAY DIFFRACTION	1.9
6MAC	X-RAY DIFFRACTION	2.34
5JHW	X-RAY DIFFRACTION	2.35
7MRZ	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95390-F1	74.49	0.30

Antibody-complex structures (SAbDab): 1 — 7MRZ

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 121–122 (cleavage; by bmp1); 298 (cleavage; by furin)

Disulfide bonds (5): 371, 304–314, 313–372, 341–404, 345–406

Glycosylation sites (1): 94

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 227 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_METANEPHROS_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, BROWNE_HCMV_INFECTION_8HR_UP, GOBP_NEUROGENESIS, GOMF_GROWTH_FACTOR_ACTIVITY, GOBP_KIDNEY_EPITHELIUM_DEVELOPMENT, GOBP_PANCREAS_DEVELOPMENT, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_ANATOMICAL_STRUCTURE_MATURATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (22): skeletal system development (GO:0001501), metanephros development (GO:0001656), ureteric bud development (GO:0001657), transforming growth factor beta receptor signaling pathway (GO:0007179), nervous system development (GO:0007399), mesoderm development (GO:0007498), cell population proliferation (GO:0008283), negative regulation of cell population proliferation (GO:0008285), spinal cord anterior/posterior patterning (GO:0021512), activin receptor signaling pathway (GO:0032924), amacrine cell differentiation (GO:0035881), camera-type eye morphogenesis (GO:0048593), roof of mouth development (GO:0060021), positive regulation of SMAD protein signal transduction (GO:0060391), type B pancreatic cell maturation (GO:0072560), negative regulation of amacrine cell differentiation (GO:1902870), signal transduction (GO:0007165), animal organ morphogenesis (GO:0009887), anterior/posterior pattern specification (GO:0009952), neuron differentiation (GO:0030182), pancreas development (GO:0031016), negative regulation of neuron differentiation (GO:0045665)

GO Molecular Function (3): cytokine activity (GO:0005125), growth factor activity (GO:0008083), protein binding (GO:0005515)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), protein-containing complex (GO:0032991), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	2
transforming growth factor beta receptor superfamily signaling pathway	2
cellular process	2
receptor ligand activity	2
kidney development	1
mesonephric tubule development	1
cellular response to transforming growth factor beta stimulus	1
tissue development	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
anterior/posterior pattern specification	1
spinal cord patterning	1
neural retina development	1
central nervous system neuron differentiation	1
camera-type eye development	1
eye morphogenesis	1
anatomical structure development	1
regulation of SMAD protein signal transduction	1
SMAD protein signal transduction	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
positive regulation of intracellular signal transduction	1
epithelial cell maturation	1
type B pancreatic cell development	1
amacrine cell differentiation	1
negative regulation of neuron differentiation	1
regulation of amacrine cell differentiation	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
anatomical structure morphogenesis	1
animal organ development	1
regionalization	1
cell differentiation	1
generation of neurons	1
binding	1
cellular_component	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1338 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GDF11	ACVR2B	Q13705	996
GDF11	ACVR2A	P27037	995
GDF11	TGFBR1	P36897	977
GDF11	ACVR1B	P36896	926
GDF11	FST	P19883	915
GDF11	ATOH7	Q8N100	904
GDF11	ACVR1C	Q8NER5	897
GDF11	WFIKKN2	Q8TEU8	870
GDF11	FSTL3	O95633	864
GDF11	ACVR1	Q04771	833
GDF11	WIF1	Q9Y5W5	833
GDF11	ACE	P12821	815
GDF11	MNX1	P50219	757
GDF11	PCSK5	Q92824	740
GDF11	WFIKKN1	Q96NZ8	715

IntAct

55 interactions, top by confidence:

A	B	Type	Score
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
GDF11	ACVR2B	psi-mi:“MI:0407”(direct interaction)	0.590
DKK3	NME4	psi-mi:“MI:0914”(association)	0.530
LIPH	LRP5	psi-mi:“MI:0914”(association)	0.530
CRP	QSOX1	psi-mi:“MI:0914”(association)	0.530
MMP26	SLC25A20	psi-mi:“MI:0914”(association)	0.530
C1QTNF9B	PLOD3	psi-mi:“MI:0914”(association)	0.530
OS9	AGRN	psi-mi:“MI:0914”(association)	0.530
GDF11	WFIKKN2	psi-mi:“MI:0915”(physical association)	0.400
WFIKKN1	GDF11	psi-mi:“MI:0915”(physical association)	0.400
Acvr1b	GDF11	psi-mi:“MI:0915”(physical association)	0.400
GDF11	Tgfbr1	psi-mi:“MI:0915”(physical association)	0.400
Acvr1c	GDF11	psi-mi:“MI:0915”(physical association)	0.400
SCGB2A2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
BMP7	VWA8	psi-mi:“MI:0914”(association)	0.350
APP	ZNF724	psi-mi:“MI:0914”(association)	0.350
LYPD4	DPYSL4	psi-mi:“MI:0914”(association)	0.350
TMEM25	FUZ	psi-mi:“MI:0914”(association)	0.350
CRP	QSOX1	psi-mi:“MI:0914”(association)	0.350
PCDHGA5	MAP2K7	psi-mi:“MI:0914”(association)	0.350
SIAE	COCH	psi-mi:“MI:0914”(association)	0.350
PRSS2	GDF11	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
OS9	GXYLT2	psi-mi:“MI:0914”(association)	0.350
FBLN5	ZNF320	psi-mi:“MI:0914”(association)	0.350
CDH23	GTPBP10	psi-mi:“MI:0914”(association)	0.350
LLCFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
GDF11	TSPY2	psi-mi:“MI:0914”(association)	0.350

BioGRID (59): GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS), GDF11 (Affinity Capture-MS)

ESM2 similar proteins: A2BD09, A4IFM1, A4IIA2, A5A6P7, D3Z7H8, F1QCC6, G3X745, O00391, O75487, O95390, P13265, P35052, P35053, P50593, P51653, P51654, P51655, P51693, P78333, P83714, Q02011, Q03157, Q0V9W0, Q2KHV9, Q3U0S6, Q5RE54, Q5U651, Q64375, Q68BL7, Q6R2R2, Q6V9Y8, Q80ZD5, Q86VZ4, Q8BH02, Q8BKV1, Q8BTG6, Q8CAL5, Q8CFZ4, Q8IUL8, Q8IYS2

Diamond homologs: A1C2U3, A1C2U6, A1C2U7, A1C2V0, A1C2V5, A8E7N9, G5EEL5, O08689, O14793, O18828, O18830, O18831, O18836, O35312, O42220, O42221, O42222, O46576, O61643, O95390, O95393, P09534, P12644, P12645, P17491, P18075, P20722, P20863, P22003, P22004, P22444, P23359, P27091, P27539, P35621, P43026, P43027, P43028, P43029, P48970

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
GDF11	up-regulates	ACTR2	binding
GDF11	up-regulates	ACVR2B	binding
FST	“down-regulates activity”	GDF11	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

52 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

508 predictions. Top by Δscore:

Variant	Effect	Δscore
12:55743757:GGAGA:G	donor_gain	1.0000
12:55743758:GAGA:G	donor_gain	1.0000
12:55743758:GAGAG:G	donor_gain	1.0000
12:55743759:A:T	donor_gain	1.0000
12:55743760:GA:G	donor_gain	1.0000
12:55743762:G:GG	donor_gain	1.0000
12:55743759:AGA:A	donor_gain	0.9900
12:55743760:GAG:G	donor_gain	0.9900
12:55743760:GAGT:G	donor_loss	0.9900
12:55743763:T:G	donor_loss	0.9900
12:55747968:G:GT	donor_gain	0.9900
12:55748584:A:AG	acceptor_gain	0.9900
12:55748585:G:GG	acceptor_gain	0.9900
12:55749492:T:TA	acceptor_gain	0.9900
12:55749496:CCTCA:C	acceptor_loss	0.9900
12:55749497:CTCA:C	acceptor_loss	0.9900
12:55749499:CAGC:C	acceptor_loss	0.9900
12:55749500:A:AG	acceptor_gain	0.9900
12:55749501:G:GG	acceptor_gain	0.9900
12:55749501:GC:G	acceptor_gain	0.9900
12:55749501:GCAT:G	acceptor_gain	0.9900
12:55749858:G:GA	donor_gain	0.9900
12:55743765:A:AG	donor_gain	0.9800
12:55743766:G:GG	donor_gain	0.9800
12:55749501:GCATC:G	acceptor_gain	0.9800
12:55749840:C:T	donor_gain	0.9800
12:55743710:G:GT	donor_gain	0.9700
12:55743713:G:GT	donor_gain	0.9700
12:55749693:C:T	donor_gain	0.9700
12:55749857:T:TA	donor_gain	0.9700

AlphaMissense

2636 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:55743552:T:A	I79N	1.000
12:55743556:G:C	K80N	1.000
12:55743556:G:T	K80N	1.000
12:55743561:A:C	Q82P	1.000
12:55743564:T:A	I83N	1.000
12:55743564:T:C	I83T	1.000
12:55743564:T:G	I83S	1.000
12:55743576:T:C	L87P	1.000
12:55743582:T:C	L89P	1.000
12:55743594:C:A	P93H	1.000
12:55748631:T:C	F164S	1.000
12:55748631:T:G	F164C	1.000
12:55748679:T:C	L180P	1.000
12:55748843:T:A	W235R	1.000
12:55748843:T:C	W235R	1.000
12:55748845:G:C	W235C	1.000
12:55748845:G:T	W235C	1.000
12:55748879:T:A	W247R	1.000
12:55748879:T:C	W247R	1.000
12:55748881:G:C	W247C	1.000
12:55748881:G:T	W247C	1.000
12:55748906:G:C	G256R	1.000
12:55749508:T:C	F284L	1.000
12:55749510:C:A	F284L	1.000
12:55749510:C:G	F284L	1.000
12:55749568:T:A	C304S	1.000
12:55749568:T:C	C304R	1.000
12:55749569:G:A	C304Y	1.000
12:55749569:G:C	C304S	1.000
12:55749569:G:T	C304F	1.000

dbSNP variants (sampled 300 via entrez): RS1000010996 (12:55753097 C>T), RS1000013356 (12:55756738 A>G), RS1000081416 (12:55742227 C>A), RS1000257431 (12:55749304 T>C), RS1000297436 (12:55753558 T>G), RS1000664279 (12:55744030 A>T), RS1000802807 (12:55756411 T>C), RS1000810614 (12:55751506 G>A,C), RS1001171420 (12:55756890 G>A), RS1001242595 (12:55743132 C>T), RS1001542389 (12:55757261 AAC>A), RS1001564887 (12:55748334 A>G), RS1001672227 (12:55743445 C>A,G), RS1002172388 (12:55744493 G>C), RS1002412370 (12:55752225 T>C,G)

Disease associations

OMIM: gene MIM:603936 | disease phenotypes: MIM:619122, MIM:119530

GenCC curated gene-disease

Disease	Classification	Inheritance
vertebral hypersegmentation and orofacial anomalies	Strong	Autosomal dominant

Mondo (3): vertebral hypersegmentation and orofacial anomalies (MONDO:0030871), neurodevelopmental disorder (MONDO:0700092), orofacial cleft (MONDO:0000358)

Orphanet (0):

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000176	Submucous cleft hard palate
HP:0000269	Prominent occiput
HP:0000286	Epicanthus
HP:0000347	Micrognathia
HP:0000349	Widow’s peak
HP:0000391	Thickened helices
HP:0000463	Anteverted nares
HP:0000592	Blue sclerae
HP:0000767	Pectus excavatum
HP:0001382	Joint hypermobility
HP:0001763	Pes planus
HP:0002558	Supernumerary nipple
HP:0003577	Congenital onset
HP:0003691	Scapular winging
HP:0005815	Supernumerary ribs
HP:0008416	Six lumbar vertebrae
HP:0011261	Darwin tubercle of helix
HP:0011800	Midface retrusion
HP:0100333	Unilateral cleft lip
HP:0100334	Unilateral cleft palate

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_217	Refractive error	6.000000e-174

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	increases expression	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
trichostatin A	affects expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butylbenzyl phthalate	increases expression	1
abrine	decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Methyl Methanesulfonate	decreases expression	1
N-Nitrosopyrrolidine	increases expression	1
Quercetin	increases expression	1
Rotenone	decreases expression	1
Dronabinol	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	increases expression	1
Okadaic Acid	increases expression	1
Acrylamide	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

207 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice